Matrix Metalloproteinase Responsive, Proximity‐Activated Polymeric Nanoparticles for siRNA Delivery

Abstract

Small interfering RNA (siRNA) has significant potential to evolve into a new class of pharmaceutical inhibitors, but technologies that enable robust, tissue-specific intracellular delivery must be developed before effective clinical translation can be achieved. A pH-responsive, smart polymeric nanoparticle (SPN) with matrix metalloproteinase (MMP)-7-dependent proximity-activated targeting (PAT) is described here. The PAT-SPN was designed to trigger cellular uptake and cytosolic delivery of siRNA once activated by MMP-7, an enzyme whose overexpression is a hallmark of cancer initiation and progression. The PAT-SPN is composed of a corona-forming PEG block, an MMP-7-cleavable peptide, a cationic siRNA-condensing block, and a pH-responsive, endosomolytic terpolymer block that drives self-assembly and forms the PAT-SPN core. With this novel design, the PEG corona shields cellular interactions until it is cleaved in MMP-7-rich environments, shifting SPNζ-potential from +5.8 to +14.4 mV and triggering a 2.5 fold increase in carrier internalization. The PAT-SPN exhibited pH-dependent membrane disruptive behavior that enabled siRNA escape from endo-lysosomal pathways. Efficient intracellular siRNA delivery and knockdown of the model enzyme luciferase in R221A-Luc mammary tumor cellssignificantly depended on MMP-7 pre-activation. These combined data indicate that the PAT-SPN provides a promising new platform for tissue-specific, proximity-activated siRNA delivery to MMP-rich pathological environments.

Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting

“…22,23 Lengthening NP residence times in the blood stream, through delaying clearance by the immune system or filtration by the kidneys, is achieved by covering the NPs with neutrally charged polymer coatings. [23][24][25][26][27] While local injection of NP-based materials is available for joint and wound therapy, 25,28,29 there are several common scenarios that require delivery to difficult-to-reach or unknown locations, such as tumors and metastatic disease. These situations often involve systemic administration through either oral ingestion or, relevant to the present study, venous injection.…”

“…30 Such approaches require that the surface of NPs be conjugated to targeting ligands to increase the odds of particle accumulation at the desired location. 26 In addition, this targeting strategy typically leverages the overexpression of enzymes, decrease in pH, 26,31,32 leakiness of the tissue, and/or enhanced tissue retention of the nanosized particles. 23,29 These features can be exploited to activate the circulating NP drug carriers at the target organ or disease site.…”

Stimuli-Responsive Polymeric Nanocarriers as Promising Drug and Gene Delivery Systems

“…Reproduced from Choi et al (2011, Copyright American Chemical Society) with permission the presence of MMP-2, the resulting PEG-sheddable polyplex micelles exhibited high transfection efficiency (Li et al 2013b). Recently, more advanced multifunctional MMP-7 triggered PEG sheddable cationic polymeric nanoparticles with a pHdependent membrane disruptive characteristic were developed (Li et al 2013a). In the presence of MMP-7, this smart nanoparticle effectively delivered siRNA into the cytosol, and enabled RNA interference and protein-level knockdown.…”

Delivery of Nucleic Acids for Cancer Gene therapy: Overcoming extra- and intra-cellular Barriers

“…In one study, the authors used an MMP-7-cleavable linker to tether PEG to polymeric nanoparticles for the delivery of anti-luciferase siRNA [48]. In vitro supplementation of MDA-MB-231 transfection medium with recombinant MMP-7 improved transfection efficiency 2.5-fold over that observed when MMP-7 was absent.…”